The research proposed in this application will explore three different strategies for tolerance induction for islet transplantation in non-human primates. The first strategy will be based on the use of a well-known co-stimulatory blocking agent, anti-CD40L, which will be used in conjunction with Donor Specific Transfusions along with other treatments such as sirolimus and anti-CD8 antibody therapy. The proposed experiments are based on the results of murine experiments that have been published from several different laboratories. They are also based on our own on-going efforts to use these reagents in non-human primates for islet transplantation to achieve an effective combination for tolerance induction. The excellent results that we have obtained so far still need to be improved to justify clinical trials. The second strategy will be based on the use of blocking reagents for a new co-stimulatory molecule called ICOS. Our murine experiments using reagents to inhibit this co-stimulatory pathway have suggested that ICOS blockade may provide additional effects beyond those achieved by inhibiting the CD40-CD40L pathway and that ICOS inhibition may be especially important in preventing T cell reponses from memory T cells. Therefore, ICOS inhibition may be especially useful in achieving allogeneic islet transplantation in the face of pre-existing autoimmunity .The excellent results that we and others have obtained in murine studies justify an extension of these experiments to non-human primates. The third strategy will be based on the use of lytic reagents directed at the IL-2Receptor and at the IL-15Receptor of activated T cells. These experiments are based partly on our improved understanding of the redundant cytokine pathways that are involved in T cell activation, and on the results of murine experiments that have shown that treatment based on a combination of these two reagents can achieve prolonged survival of allogeneic islets without on-going immunosuppression, even in diabetic NOD mice.